CN114028347A - Parecoxib sodium for injection and preparation method thereof - Google Patents
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- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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Abstract
The invention provides parecoxib sodium for injection and a preparation method thereof, and belongs to the technical field of medicine preparation. According to the injection, the mannitol and the lactose are mutually compatible and are jointly used as an excipient, so that the hygroscopicity of the parecoxib sodium for injection can be effectively inhibited, and the medicine stability of the parecoxib sodium is improved.
Description
Technical Field
The invention relates to preparation of sterile powder injection, in particular to parecoxib sodium for injection and a preparation method thereof.
Background
The parecoxib sodium for injection is a non-steroidal anti-inflammatory drug, mainly has the functions of analgesia and anti-inflammation, and is a selective cyclooxygenase-2 inhibitor. Cyclooxygenase participates in the synthesis of prostaglandins, and it has been found that cyclooxygenase has two isomers, including cyclooxygenase-1 and cyclooxygenase-2. Studies have shown that cyclooxygenase-2 is produced as a cyclooxygenase isomer induced by inflammatory stimuli, and thus cyclooxygenase-2 plays a major role in the synthesis of prostaglandin-like mediators involved in pain, inflammation and fever. The parecoxib sodium mainly has the functions of analgesia and anti-inflammation through inhibiting cyclooxygenase-2. The parecoxib sodium for clinical injection is mainly used for relieving pain and is suitable for analgesic treatment of short-term pain after operation.
The parecoxib sodium is white or white-like crystalline powder and has certain hygroscopicity, parecoxib sodium is easy to degrade in a water environment to become valdecoxib, and valdecoxib is poor in water solubility and cannot be completely dissolved in an injection dissolving process, so that the use curative effect is influenced, and the change of the moisture absorption characteristic of the parecoxib sodium for injection is beneficial to improvement of the stability of the parecoxib sodium, and further the drug effect is improved.
Parecoxib sodium is a sodium salt of benzenesulfonamide, which structurally has diphenyl-substituted rings and a heterocycle. At present, the synthesis method mainly takes the diphenylethanone or the 1-phenyl-2-acetone as the starting raw material for synthesis, and the synthesis route mainly comprises the following steps:
in the first method, document WO2005123701 uses diphenylethanone as a raw material, the diphenylethanone reacts with pyrrolidine to obtain an intermediate 2, the intermediate 2 is acetylated to obtain an intermediate 3, the intermediate 4 is cyclized to obtain an intermediate 4, the intermediate 4 is dehydrated by trifluoroacetic acid to obtain an important intermediate 5 (i.e., a compound iii, 5-methyl-3, 4-diphenylisoxazole), then an intermediate 6 (valdecoxib) is obtained through sulfonylation and ammoniation reactions, and finally propionylation and salification are carried out to obtain parecoxib sodium, which specifically comprises the following steps:
in the second route, document CN102329277 also uses acetophenone as a raw material, and first performs a sulfonylation reaction to obtain an intermediate 8, then performs an acetylation reaction and a cyclization reaction to obtain an intermediate 10, and performs a sulfonylation reaction and an amination reaction to obtain an intermediate 6 (valdecoxib), and finally performs a propionylation reaction and a salt forming reaction to obtain a final product parecoxib sodium, wherein the synthetic route is as follows:
the third route, document WO2005/085218, using 5-methyl-3, 4-diphenylisoxazole intermediate 5 as the starting material, adding oleum to perform sulfonation reaction, then forming sodium sulfonate, performing acyl chlorination and ammoniation to obtain intermediate 6 (valdecoxib), the synthetic route is as follows:
the fourth route is that the intermediate 14 (4-iodo-5-methyl-3-phenylisoxazole) is obtained by a cyclization reaction of the compound 13 (4-phenyl-3-butyne 2-oxoisobutyramide), and the intermediate 14 and the compound 15 (4-sulfonylaminobenzeneboronic acid) react to obtain the intermediate 6 (valdecoxib), and the synthetic route is as follows:
by integrating the various synthesis schemes, in the synthesis process of parecoxib sodium at present, an intermediate 6 (valdecoxib) is synthesized firstly, and then propionylation and salt-forming reaction are carried out to obtain parecoxib sodium, but the synthesis of the valdecoxib sodium is found to be unnecessary through the research on the synthesis process of the parecoxib sodium, so that the parecoxib sodium is synthesized by taking 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonic acid as a raw material through improvement on the basis of a route II, the reaction steps are reduced, the reaction time is shortened, and the reaction yield is improved.
Disclosure of Invention
Aiming at the problems, the invention provides parecoxib sodium for injection and a preparation method thereof.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
the parecoxib sodium for injection is prepared from the following raw materials as effective components: 10 parts of parecoxib sodium, 0.5-1 part of disodium hydrogen phosphate, 1-1.5 parts of mannitol and 3-4 parts of lactose.
Further, the parecoxib sodium is prepared by synthesizing 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonic acid and propionamide by a DCC method, and performing salt forming reaction on the obtained parecoxib and sodium hydroxide.
Further, the specific synthesis method of the parecoxib sodium comprises the following steps:
1) preparation of parecoxib
Dissolving 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonic acid in an organic solvent, and then sequentially adding a catalyst, propionamide, dicyclohexylcarbodiimide (DCC for short) and a condensing agent to perform sulfonylation reaction to obtain parecoxib, wherein the specific chemical reaction formula is as follows:
2) preparation of parecoxib sodium
Carrying out salt forming reaction on parecoxib and sodium hydroxide to obtain parecoxib sodium, wherein the specific chemical reaction formula is as follows:
further, in the step 1), the catalyst is 4-dimethylamino pyridine.
Further, in the step 1), the condensing agent is 1-hydroxy phenylpropyl triazole; the organic solvent is dichloromethane;
in the step 2), the solvent for salt forming reaction is methanol or ethanol.
Further, in the step 1), the molar ratio of the 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonic acid to the catalyst to the propionamide to the dicyclohexylcarbodiimide to the condensing agent is 1: 0.08-0.2: 1.1-1.2: 1.08-1.16: 1.1 to 1.16.
Further, in the step 2), the molar ratio of the parecoxib to the sodium hydroxide is 1: 1.1 to 1.2.
Further, in the step 1), the temperature of the sulfonylation reaction is-5 ℃;
in the step 2), the temperature of the salt forming reaction is 60-70 ℃.
A preparation method of parecoxib sodium for injection comprises the steps of dissolving all raw materials in sufficient amount of water, decoloring, fixing volume, adjusting pH value, sterilizing, filtering and freeze-drying to obtain the parecoxib sodium for injection.
Further, the pH regulator for regulating the pH is phosphoric acid aqueous solution/sodium hydroxide aqueous solution.
The parecoxib sodium for injection and the preparation method thereof have the beneficial effects that:
according to the injection, the mannitol and the lactose are mutually compatible and are used as the excipient, so that the hygroscopicity of the parecoxib sodium for injection can be effectively inhibited, and the medicine stability is improved;
the method takes 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonic acid as a raw material, utilizes a DCC method to directly synthesize parecoxib, does not need to prepare valdecoxib, reduces the original 3-step reaction into 2 steps, saves the reaction time, reduces the production cost, improves the reaction yield, has mild reaction conditions, adopts a low-toxicity and non-toxic reagent, generates less three wastes, is relatively friendly to the environment, and is suitable for industrial production.
Detailed Description
The technical solutions in the embodiments of the present invention are clearly and completely described below. In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, but the present invention may be practiced in other ways than those specifically described and will be readily apparent to those of ordinary skill in the art without departing from the spirit of the present invention, and therefore the present invention is not limited to the specific embodiments disclosed below.
Example 1 Synthesis method of parecoxib sodium
The embodiment is a synthesis method of parecoxib sodium, and the specific preparation process comprises the following steps in sequence:
1) preparation of parecoxib
11) Preparation of 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonic acid
Dissolving 196.2g (1mol) of 1, 2-diphenylethanone in 2L of acetone, cooling to 0 ℃, slowly dropwise adding 116.5g (1mol) of chlorosulfonic acid, naturally heating to room temperature after dropwise adding, maintaining the room temperature, continuously stirring for reaction for 5 hours, evaporating acetone after the reaction is finished, adding 1L of water into obtained residues, carrying out reflux reaction for 12 hours, cooling, extracting with ethyl acetate, drying with anhydrous sodium sulfate, filtering, concentrating, cooling and crystallizing to obtain 199.2g of white crystalline powdery 1 phenyl 2 (4-sulfophenyl) ethanone, wherein the yield is 72.1%, and the specific chemical reaction formula is as follows:
193.41g (0.7mol) of 1 phenyl 2(4 sulfophenyl) ethanone is added into 1.2L of pyridine, stirred and dissolved, then cooled to 0 ℃, 55.0g (0.7mol) of acetyl chloride is slowly dropped, stirred and reacted for 1h under the condition of maintaining 0 ℃, then naturally heated to 50 ℃, maintained at 50 ℃ for 2h, decompressed and concentrated after the reaction is finished to remove pyridine, the obtained residue is poured into ice water, filtered, the obtained filter cake is washed by water and methanol in sequence and dried to obtain 157.8g of 1 phenyl 2(4 sulfophenyl) 2 acetyl ethanone in light yellow solid powder, the yield is 70.8%, and the specific chemical reaction formula is as follows:
143.3g (0.47mol) of 1 phenyl 2(4 sulfophenyl) 2 acetyl acetone is dissolved in 1.8L ethanol, 32.7g (0.47mol) of hydroxylamine hydrochloride is added in 5 times, the mixture is heated to 78 ℃ for reaction for 8h, and after the reaction is finished, the mixture is cooled and crystallized to obtain 88.5g of white solid powdery 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonic acid, wherein the yield is 62.5 percent, and the specific chemical reaction formula is as follows:
12) preparation of parecoxib
75.33g (0.25mol) of 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonic acid is dissolved in 400mL of dichloromethane, then 3.05g (0.025mol) of 4-dimethylaminopyridine is added, stirring and pre-reaction is carried out for 15min, then the temperature is reduced to 0 ℃, 20.1g (0.275mol) of propionamide is added in 3 batches, then 56.74g (0.275mol) of dicyclohexylcarbodiimide and 37.16g (0.275mol) of 1-hydroxy phenylpropyl triazole are added, sulfonylation reaction is carried out for 6h under the condition of maintaining the temperature at 0 ℃, after the reaction is finished, the solution is filtered, 100mL multiplied by 2 of water is washed, anhydrous magnesium sulfate is dried and concentrated, and the obtained crude product is recrystallized by ethanol to obtain 70.12g of white crystalline powdery parecoxib, the yield is 80.13%, and the specific chemical reaction formula is as follows:
2) preparation of parecoxib sodium
6.6g (0.165mol) of sodium hydroxide is dissolved in 150mL of absolute ethyl alcohol to obtain a sodium hydroxide alcohol solution for later use;
adding 55.56g (0.15mol) of parecoxib into 100mL of absolute ethanol, stirring and heating to 60 ℃, then slowly dropwise adding a sodium hydroxide alcohol solution, after dropwise adding, maintaining the temperature of 60 ℃ for reaction for 1h, then slowly cooling to 0 ℃, maintaining the temperature of 0 ℃, stirring and crystallizing for 5h, filtering, washing with 50mL of x 2 glacial ethanol, and drying to obtain 58.86g of white powdery parecoxib sodium, wherein the mark is M1, the yield is 90.25%, the purity is 99.6%, and the specific chemical reaction formula is as follows:
example 2-5 Synthesis method of parecoxib sodium
Examples 2 to 5 are methods for synthesizing parecoxib sodium, which have substantially the same steps as example 1, but differ only in the amount of raw materials and process parameters, as detailed in table 1:
TABLE 1 summary of the process parameters of examples 2 to 5
The contents of the other portions of examples 2 to 5 are the same as those of example 1.
Embodiment 6 preparation method of parecoxib sodium for injection
The embodiment is a preparation method of parecoxib sodium for injection, and the specific preparation process comprises the following steps of:
boiling water for injection, and cooling;
adding 3.39kg of disodium hydrogen phosphate into 1.5L of water for injection at room temperature, stirring the solution, adjusting the pH value to 8.2 by using 0.1mol/L aqueous solution of phosphoric acid, then adding 42.37kg of parecoxib sodium M1, 4.24kg of mannitol and 14.83kg of lactose (the weight ratio BL between parecoxib sodium, disodium hydrogen phosphate, mannitol and lactose is 10: 0.8: 1: 3.5), stirring the solution until the solution is dissolved, adding 0.4kg of medicinal active carbon, stirring the solution at room temperature for decoloring for 30min, filtering the solution, supplementing water to 2L (constant volume), measuring the pH value, adjusting the pH value to 8.2 again by using 0.1mol/L aqueous solution of phosphoric acid or 0.1mol/L aqueous solution of sodium hydroxide, filtering the solution by using a 0.22 mu M primary sterilizing filter, and filtering the solution by using 0.22 mu M secondary terminal sterilizing filter to effectively remove fine bacteria microorganisms to obtain sterile liquid medicine for later use;
filling the sterile liquid medicine according to the required specification (specification 40mg (in terms of parecoxib sodium)), filling the sterile liquid medicine in a semi-filling manner, transferring the sterile liquid medicine into a freeze dryer for vacuum freeze drying, wherein the vacuum freeze drying comprises prefreezing, sublimation drying and analytical drying;
pre-freezing: firstly, cooling a product in a freeze-drying machine case to-40 ℃, and pre-freezing for 2 hours at the temperature of-40 ℃;
sublimation drying: vacuumizing to make the pressure in the box be 10Pa, heating to-20 ℃ at the speed of 5 ℃/h, and carrying out first sublimation drying for 2 h;
keeping the pressure in the box at 10Pa, heating to 0 ℃ at the speed of 5 ℃/h, and carrying out secondary sublimation drying for 3 h;
and (3) resolving and drying: keeping the pressure in the box at 10Pa, heating to 15 ℃ at the speed of 5 ℃/h, and carrying out primary analysis and drying for 1 h;
keeping the pressure in the box at 10Pa, heating to 30 ℃ at 5 ℃/h, and carrying out secondary analysis and drying for 3 h.
Example 7-10 preparation method of parecoxib sodium for injection
Examples 7 to 10 are methods for preparing parecoxib sodium for injection, which have substantially the same steps as example 1, but differ only in the amount of raw materials and process parameters, as detailed in table 2:
TABLE 2 summary of the process parameters of examples 7 to 10
The contents of the other portions of examples 7 to 10 are the same as those of example 6.
The parecoxib sodium for injection prepared in the embodiments 7-10 is good in stability, high in main drug content, few in impurities and good in re-solubility.
Experimental example 1 Performance measurement of parecoxib sodium
Comparative example 1 according to the method disclosed in the patent publication No. CN102329277B, valdecoxib was synthesized first using 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonic acid as a starting material, and parecoxib was synthesized with a total yield of 72.16%.
The synthesis method of the embodiments 1 to 5 of the invention uses 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonic acid as a raw material to synthesize parecoxib, and the yield reaches 69.27% -81.82%.
Experimental example 2 Performance measurement of parecoxib sodium for injection
Comparative examples 2 to 3 are comparative tests of the preparation process of parecoxib sodium for injection [ specification 40mg (in terms of parecoxib sodium) ] in example 6, and the differences are only that:
in comparative example 2, 19.07kg of mannitol was used as an excipient instead of 4.24kg of mannitol and 14.83kg of lactose;
in comparative example 3 19.07kg of lactose was used as excipient instead of 4.24kg of mannitol and 14.83kg of lactose.
a1) Accelerated test
The parecoxib sodium for injection prepared in the examples 6-10 and the comparative examples 2-3 is respectively placed under the conditions of 40 +/-2 ℃ and RH75 +/-5% for 24 months, samples are respectively sampled and detected at 1 st, 3 th, 6 th, 12 th and 24 th months in the period (according to ' detection of related substances in parecoxib sodium for injection by high performance liquid chromatography ' Lichangliang, Chinese pharmacy 2014 '), and compared with the day 0 data, the specific detection result is shown as follows:
TABLE 3 summary of test results of accelerated test
As can be seen from Table 3, the parecoxib sodium for injection prepared in the embodiments 1 to 6 of the invention has the advantages that the moisture content is obviously lower than that of the parecoxib sodium for injection in the comparative examples 2 to 3, the stability is high, and the content of related substances is low, which indicates that the technological parameters of the invention can inhibit the hygroscopicity of the parecoxib sodium for injection, and the parecoxib sodium for injection is convenient to prepare and store.
a2) Resolubility detection
The parecoxib sodium for injection prepared in the embodiments 1-6 and the comparative examples 2-3 is taken, 2mL of water for injection is respectively added for dissolution, the dissolution speed is observed, and the specific test results are shown in the following table:
TABLE 4 summary of the results of the redissolution test
As can be seen from Table 4, the parecoxib sodium for injection prepared in the embodiments 6-10 of the invention has good re-solubility.
It is to be understood that the described embodiments are merely a few embodiments of the invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Claims (10)
1. The parecoxib sodium for injection is characterized in that raw materials for preparing active ingredients of the parecoxib sodium for injection comprise: 10 parts of parecoxib sodium, 0.5-1 part of disodium hydrogen phosphate, 1-1.5 parts of mannitol and 3-4 parts of lactose.
2. The parecoxib sodium for injection according to claim 1, wherein the parecoxib sodium is prepared by synthesizing 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonic acid and propionamide by a DCC method, and performing salt formation reaction on the obtained parecoxib and sodium hydroxide.
3. The parecoxib sodium for injection according to claim 2, wherein the specific synthesis method of the parecoxib sodium comprises the following steps:
1) preparation of parecoxib
Dissolving 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonic acid in an organic solvent, and then sequentially adding a catalyst, propionamide, dicyclohexylcarbodiimide and a condensing agent to perform sulfonylation reaction to obtain parecoxib, wherein the specific chemical reaction formula is as follows:
2) preparation of parecoxib sodium
Carrying out salt forming reaction on parecoxib and sodium hydroxide to obtain parecoxib sodium, wherein the specific chemical reaction formula is as follows:
4. the parecoxib sodium for injection according to claim 3, wherein the catalyst used in step 1) is 4-dimethylaminopyridine.
5. The parecoxib sodium for injection according to claim 3 or 4, wherein the condensing agent in step 1) is 1-hydroxy phenylpropyl triazole.
6. Parecoxib sodium for injection according to claim 3 or 4, wherein in step 1), the molar ratio of 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonic acid, catalyst, propionamide, dicyclohexylcarbodiimide and condensing agent is 1: 0.08-0.2: 1.1-1.2: 1.08-1.16: 1.1 to 1.16.
7. Parecoxib sodium for injection according to claim 3 or 4, wherein the molar ratio of parecoxib to sodium hydroxide in step 2) is 1: 1.1 to 1.2.
8. Parecoxib sodium for injection according to claim 3 or 4,
in the step 1), the temperature of the sulfonylation reaction is-5 ℃;
in the step 2), the temperature of the salt forming reaction is 60-70 ℃.
9. The preparation method of parecoxib sodium for injection according to any one of claims 1-8, wherein the parecoxib sodium for injection is prepared by dissolving all raw materials in sufficient amount of water, decoloring, fixing volume, adjusting pH value, sterilizing, filtering and lyophilizing.
10. The method for preparing parecoxib sodium for injection according to claim 9, wherein the pH adjuster for adjusting pH is an aqueous phosphoric acid solution/aqueous sodium hydroxide solution.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101541310A (en) * | 2006-12-13 | 2009-09-23 | 弗·哈夫曼-拉罗切有限公司 | Powder formulations of valganciclovir |
| CN104771370A (en) * | 2014-01-14 | 2015-07-15 | 南京圣和药业股份有限公司 | Parecoxib sodium freeze-dried powder injection and preparation method thereof |
| CN111150709A (en) * | 2020-03-17 | 2020-05-15 | 天津梅花生物医药科技有限公司 | Methylprednisolone sodium succinate for injection and preparation method thereof |
| CN113230218A (en) * | 2021-04-30 | 2021-08-10 | 雅本化学股份有限公司 | Ca-AKG chewable tablet and preparation method thereof |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101541310A (en) * | 2006-12-13 | 2009-09-23 | 弗·哈夫曼-拉罗切有限公司 | Powder formulations of valganciclovir |
| CN104771370A (en) * | 2014-01-14 | 2015-07-15 | 南京圣和药业股份有限公司 | Parecoxib sodium freeze-dried powder injection and preparation method thereof |
| CN111150709A (en) * | 2020-03-17 | 2020-05-15 | 天津梅花生物医药科技有限公司 | Methylprednisolone sodium succinate for injection and preparation method thereof |
| CN113230218A (en) * | 2021-04-30 | 2021-08-10 | 雅本化学股份有限公司 | Ca-AKG chewable tablet and preparation method thereof |
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